8anf: Difference between revisions
No edit summary |
No edit summary |
||
| Line 5: | Line 5: | ||
<table><tr><td colspan='2'>[[8anf]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8ANF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8ANF FirstGlance]. <br> | <table><tr><td colspan='2'>[[8anf]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8ANF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8ANF FirstGlance]. <br> | ||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.4Å</td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.4Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=N1R:2-chloranyl-N-[3-[1-[2-(4-chloranylphenoxy)-2-methyl-propanoyl]piperidin-4-yl]propyl]ethanamide'>N1R</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr> | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=N1R:2-chloranyl-~{N}-[3-[1-[2-(4-chloranylphenoxy)-2-methyl-propanoyl]piperidin-4-yl]propyl]ethanamide'>N1R</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8anf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8anf OCA], [https://pdbe.org/8anf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8anf RCSB], [https://www.ebi.ac.uk/pdbsum/8anf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8anf ProSAT]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8anf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8anf OCA], [https://pdbe.org/8anf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8anf RCSB], [https://www.ebi.ac.uk/pdbsum/8anf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8anf ProSAT]</span></td></tr> | ||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
Latest revision as of 12:45, 9 October 2024
Small molecule stabilizer for ERalpha and 14-3-3 (1074359)Small molecule stabilizer for ERalpha and 14-3-3 (1074359)
Structural highlights
Publication Abstract from PubMedThe stabilization of protein-protein interactions (PPIs) has emerged as a promising strategy in chemical biology and drug discovery. The identification of suitable starting points for stabilizing native PPIs and their subsequent elaboration into selective and potent molecular glues lacks structure-guided optimization strategies. We have previously identified a disulfide fragment that stabilized the hub protein 14-3-3sigma bound to several of its clients, including ERalpha and C-RAF. Here, we show the structure-based optimization of the nonselective fragment toward selective and highly potent small-molecule stabilizers of the 14-3-3sigma/ERalpha complex. The more elaborated molecular glues, for example, show no stabilization of 14-3-3sigma/C-RAF up to 150 muM compound. Orthogonal biophysical assays, including mass spectrometry and fluorescence anisotropy, were used to establish structure-activity relationships. The binding modes of 37 compounds were elucidated with X-ray crystallography, which further assisted the concomitant structure-guided optimization. By targeting specific amino acids in the 14-3-3sigma/ERalpha interface and locking the conformation with a spirocycle, the optimized covalent stabilizer 181 achieved potency, cooperativity, and selectivity similar to the natural product Fusicoccin-A. This case study showcases the value of addressing the structure, kinetics, and cooperativity for molecular glue development. Structure-Based Optimization of Covalent, Small-Molecule Stabilizers of the 14-3-3sigma/ERalpha Protein-Protein Interaction from Nonselective Fragments.,Konstantinidou M, Visser EJ, Vandenboorn E, Chen S, Jaishankar P, Overmans M, Dutta S, Neitz RJ, Renslo AR, Ottmann C, Brunsveld L, Arkin MR J Am Chem Soc. 2023 Sep 20;145(37):20328-20343. doi: 10.1021/jacs.3c05161. Epub , 2023 Sep 7. PMID:37676236[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|
| ||||||||||||||||||